1. Field of the Invention
The present invention relates generally to methods and composition for the treatment of pain, more specifically compounds, compositions comprising the compounds, and methods for acute and chronic pain relief and acute and chronic intervention for drug abuse.
2. Description of the Related Art
Opioids are still the main analgesics for both acute and chronic pain states in clinical medication. Pain is caused by a highly complex perception of an aversive or unpleasant sensation, and represents an integrated, complex, perception of noxious stimuli originating from somatic elements such as arms and legs and/or from visceral organs such as heart and liver. The opioid drugs are widely used following major surgery and to control pain of terminal diseases such as cancer, but its use is limited by several undesired side effects including nausea, vomiting, constipation, dizziness, system changes (neuroplasticity) due to prolonged pain or treatment by the opioid drugs and the development of tolerance and physical dependence, which mainly come through the μ opioid receptor (Ananthan, J. Med. Chem., 47:1400-12, 2004; Yaksh, Pain, 11:293-346, 1981; Ossipov, Biopolymers, 80:319-24, 2005). Because of these limitations, the search for the novel type of analgesics which have strong pain controlling effect without development of tolerance and/or physical dependence has been performed for decades (Gentilucci, Curr. Topics in Med. Chem., 4:19-38, 2004).
Opiates work in the brain at specific “opiate receptors.” Several types of the opiate receptors are known, but the main receptor is called μ receptor. Administering receptor agonists can cause full or partial stimulation or effect at the receptor, while administering antagonists blocks the effect of the receptor. It is widely accepted that a μ receptor agonist such as morphine has higher antinociceptive activity accompanied with high abuse liability. On the other hand, the activation of the δ opioid receptor has lower analgesic efficacy, but has reduced addictive potential (Kaslo, Eur. J. Pain, 9:131-5, 2005). It is also generally known that the selective agonists at the δ opioid receptor have analgesic activity in numerous animal models with fewer adverse effects, though their efficacy is less potent than that of their widely-used μ counterparts (Ananthan, J. Med. Chem., 47:1400-12, 2004; Yaksh, Pain, 11:293-346, 1981; Ossipov, Biopolymers, 80:319-24, 2005). Thus, selective δ opioid agonists with enhanced analgesic activity are expected as a potent drug candidate for severe pain control.
Substance P is the preferred ligand for the neurokinin 1 (NK1) receptor and is known to contribute to chronic inflammatory pain and participate in central sensitization and associated hyperalgesia. In the pain states, substance P, which is a 11-amino acid polypeptide, is known as a major neurotransmitter of pain signals as well as the signals induced by opioid stimulation (Ananthan, J. Med. Chem., 47:1400-12, 2004; Yaksh, Pain, 11:293-346, 1981; Ossipov, Biopolymers, 80:319-24, 2005). Substance P and NK1 receptor expression increases after sustained opioid administration. Also, repeated morphine exposure results in enhanced levels of substance P both in vitro and in vivo, which could induce increased pain; increased pain could require increased pain-relief and thus be manifested as “antinociceptive tolerance” (King, Neurosignals, 14:194-205, 2005). Interestingly, co-administration of δ/μ opioid agonists and a substance P antagonist showed enhanced antinociceptive effect in acute pain states, and in prevention of opioid-induced tolerance in chronic trials. These results suggest that the signals through opioid receptors and neurokinin 1 (NK1) receptors are not independent, but have strong and critical interaction. Moreover, the mice lacking NK1 receptors, the preferred receptor of substance P, didn't show rewarding properties for opiates (Ananthan, J. Med. Chem., 47:1400-12, 2004).
According to these observations, the use of multimodal combination analgesic therapies or therapies with single molecules possessing multiple analgesic targets has become attractive (Walker, Anesth. Analg., 95:674-715, 2002). Advantages of hybrid compounds system are developing bioactive compounds designed with a broad spectrum of receptor affinities and single administration of a chimeric compound instead of a specific ration of two different compounds. Table A below provides representative listing of opioid analgesics with respect to affinity for the opioid receptors and the NK1 receptor.
TABLE APrevious Studies of Chimeric compoundsAffinity (Ki in nM)CompoundsSequenceDORMORrNK1ESP6HTyrProPhePheProLeuMetNH2—92305(SEQ ID NO: 1)ESP7HTyrProPhePheGlyLeuMetNH2—218289(SEQ ID NO: 2)JSOH11HTyrDAlaDTrpPheDTrpLeuLeuNH216.51647320JSOH9HTyrDAlaDPhePheDTrpLeuMetNH20.726062940AA501HTyrDAlaGlyPheNHNHTrpCbz—805000
Many classes of C-terminal modified compounds have attracted the inventors' interest, and a number of approaches to modifying the C-terminal have been reported (Sasubilli, J. Comb. Chem., 6:911-15, 2004; Alsina, Biopol., 71:454-77, 2003; Chan, Fmoc solid phase compound synthesis as practical approach, Oxford Univ. Press: New York, USA, 2000). These approaches can be classified into many categories including nucleophilic cleavage of protected compounds bound from appropriate resins, attachment with a C-terminal functional group, side chain anchoring followed by normal solid phase N-to-C peptide synthesis, backbone amide attachment onto a solid support, inverse C-to-N solid phase biopolymer synthesis, and conventional solution phase synthesis (Alsina, Biopolymers, 71:454-77, 2003). However, it is difficult to synthesize C-terminal esters or tertiary amides by the first two methods, and designed compounds didn't have a suitable side chain moiety to anchor on a resin. Repeated inverse C-to-N coupling leads to severe racemization, and conventional Boc solution phase compound synthesis is very labor intensive for large amounts of longer compounds.
The importance of interactions between biologically active compounds and membrane has become increasingly appreciated recently. The strong influence of these interactions on ligand activity, membrane permeability and toxicity has been increasingly clarified
(Seydel, Drug-Membrane interaction; Wiley-VCH: Weinheim, Germany, 2003, pp. 1-31). Among these compounds, peptides function as transmitters of many unique and diverse biological signals which largely depend on their amino acid sequence, and their interactions with membrane localized receptor/acceptors. However, the signal transduction of compounds is made not by the primary sequence but by higher order dynamic three-dimensional conformations. Therefore, the changes in 3D structure and dynamics which are induced by the modification of primary sequence have been a long-term interest, since 3D structure and the dynamics have an influence on the biological properties. In fact, many G-protein coupled receptors (GPCRs), which are the typical membrane-bound proteins, generally have their ligand binding site in the hydrophobic trans-membrane (TM) domains (Berthold, Neurochem. Res., 22(8):1023-31, 1997; Noeskea, QSAR Comb. Sci., 25(2):134-146, 2006; Eguchi, Med. Res. Rev., 24(20):182-212, 2004; Cascieri, J. Biol. Chem., 269:6587-91, 1994). Compound-membrane interaction also is very important when a compound penetrates membranes, such as the blood brain barrier (Seydel, Drug-Membrane Interaction; Wiley-VCH: Weinheim, Germany, 2003, pp. 1-31; Palian, J. Am. Chem. Soc., 125:5823-31, 2003). Hence, understanding of the membrane-bound structures of compounds and compound-membrane interactions is indispensable to obtain further insight into their diverse biological behaviors.